rs140764964

Variant names:

• chrX-91876958-A-T
• rs140764964
• NM_032968.5:c.718A>T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_032968.5(PCDH11X):​c.718A>T​(p.Thr240Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000252 in 1,208,038 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 99 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., 5 hem., cov: 20)
  • Exomes 𝑓: 0.00025 (0 hom. 94 hem.)
• Consequence: PCDH11X NM_032968.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 3.02
• Publications: 0 publications found

Genes affected

PCDH11X (HGNC:8656): (protocadherin 11 X-linked) This gene belongs to the protocadherin gene family, a subfamily of the cadherin superfamily. The encoded protein consists of an extracellular domain containing 7 cadherin repeats, a transmembrane domain and a cytoplasmic tail that differs from those of the classical cadherins. The gene is located in a major X/Y block of homology and its Y homolog, despite divergence leading to coding region changes, is the most closely related cadherin family member. The protein is thought to play a fundamental role in cell-cell recognition essential for the segmental development and function of the central nervous system. Disruption of this gene may be associated with developmental dyslexia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jun 2014]

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.13381535).
• BP6: Variant X-91876958-A-T is Benign according to our data. Variant chrX-91876958-A-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1087134.
• BS2: High Hemizygotes in GnomAd4 at 5 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032968.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCDH11X	NM_032968.5	MANE Select	c.718A>T	p.Thr240Ser	missense	Exon 6 of 11	NP_116750.1	Q9BZA7-1
	PCDH11X	NM_001168360.1		c.718A>T	p.Thr240Ser	missense	Exon 2 of 6	NP_001161832.1	Q9BZA7-8
	PCDH11X	NM_032969.4		c.718A>T	p.Thr240Ser	missense	Exon 2 of 6	NP_116751.1	Q9BZA7-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCDH11X	ENST00000682573.1	MANE Select	c.718A>T	p.Thr240Ser	missense	Exon 6 of 11	ENSP00000507225.1	Q9BZA7-1
	PCDH11X	ENST00000373094.5	TSL:1	c.718A>T	p.Thr240Ser	missense	Exon 2 of 7	ENSP00000362186.1	Q9BZA7-1
	PCDH11X	ENST00000406881.3	TSL:1	c.718A>T	p.Thr240Ser	missense	Exon 2 of 6	ENSP00000384758.1	Q9BZA7-8

Frequencies

GnomAD3 genomes AF: 0.000300 AC: 33 AN: 109904 Hom.: 0 Cov.: 20

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000494

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000352

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000473

Gnomad OTH AF: 0.000674

GnomAD2 exomes AF: 0.000229 AC: 42 AN: 183292 AF XY: 0.000162

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000109

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000500

Gnomad NFE exome AF: 0.000367

Gnomad OTH exome AF: 0.000221

GnomAD4 exome AF: 0.000247 AC: 271 AN: 1098091 Hom.: 0 Cov.: 31 AF XY: 0.000259 AC XY: 94 AN XY: 363565

African (AFR) AF: 0.0000379 AC: 1 AN: 26397

American (AMR) AF: 0.000114 AC: 4 AN: 35200

Ashkenazi Jewish (ASJ) AF: 0.0000516 AC: 1 AN: 19384

East Asian (EAS) AF: 0.00 AC: 0 AN: 30205

South Asian (SAS) AF: 0.00 AC: 0 AN: 54143

European-Finnish (FIN) AF: 0.000543 AC: 22 AN: 40534

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4132

European-Non Finnish (NFE) AF: 0.000280 AC: 236 AN: 842010

Other (OTH) AF: 0.000152 AC: 7 AN: 46086

GnomAD4 genome AF: 0.000300 AC: 33 AN: 109947 Hom.: 0 Cov.: 20 AF XY: 0.000156 AC XY: 5 AN XY: 32137

African (AFR) AF: 0.00 AC: 0 AN: 30253

American (AMR) AF: 0.000493 AC: 5 AN: 10133

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2642

East Asian (EAS) AF: 0.00 AC: 0 AN: 3504

South Asian (SAS) AF: 0.00 AC: 0 AN: 2528

European-Finnish (FIN) AF: 0.000352 AC: 2 AN: 5676

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 214

European-Non Finnish (NFE) AF: 0.000473 AC: 25 AN: 52808

Other (OTH) AF: 0.000665 AC: 1 AN: 1503

Alfa AF: 0.000218 Hom.: 1

Bravo AF: 0.000287

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000743 AC: 5

ExAC AF: 0.000206 AC: 25

EpiCase AF: 0.000273

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	6.4
DANN	Benign	0.77
DEOGEN2	Benign	0.032	T
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.52	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
PhyloP100		3.0
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.088
Sift	Benign	0.69	T
Sift4G	Benign	0.70	T
Polyphen		0.0090	B
Vest4		0.098
MutPred		0.52		Gain of disorder (P = 0.0553)
MVP		0.72
MPC		1.0
ClinPred		0.040	T
GERP RS		-0.33
Varity_R		0.074
gMVP		0.15
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs140764964; hg19: chrX-91131957;